Mianserin suppresses R-spondin 2-induced activation of Wnt/β-catenin signaling in chondrocytes and prevents cartilage degradation in a rat model of osteoarthritis

Scientific Reports
Toshiaki OkuraKinji Ohno

Abstract

Aberrant activation of the Wnt/β-catenin signaling pathway promotes the progression of osteoarthritis (OA). We previously reported that R-spondin 2 (Rspo2), an activator of the Wnt/β-catenin signaling, facilitates differentiation of proliferating chondrocytes into hypertrophic chondrocytes by enhancing Wnt/β-catenin signaling in endochondral ossification. However, the role of Rspo2 in OA remains elusive. Here, we showed that the amounts of Rspo2 protein in synovial fluid were increased in OA patients. We searched for a preapproved drug that suppresses Rspo2-induced Wnt/β-catenin signaling in chondrogenic cells and reduces joint pathology in a rat model of OA. In Rspo2-treated ATDC5 cells, mianserin, a tetracyclic antidepressant, inhibited Wnt/β-catenin signaling, increased proteoglycan production, and upregulated chondrogenic marker genes. Mianserin suppressed Rspo2-induced accumulation of β-catenin and phosphorylation of Lrp6. We identified that mianserin blocked binding of Rspo2 to its receptor Lgr5. We also observed that intraarticular administration of mianserin suppressed β-catenin accumulation and prevented OA progression in a rat model of OA. We conclude that mianserin suppresses abnormally activated Wnt/β-catenin signal...Continue Reading

References

Sep 4, 1998·Science·T C HeK W Kinzler
Dec 26, 2001·Proceedings of the National Academy of Sciences of the United States of America·D YanL T Williams
May 10, 2002·Nature·Alison Abbott
Dec 1, 1957·Annals of the Rheumatic Diseases·J H KELLGREN, J S LAWRENCE
Jun 11, 2005·The Journal of Biological Chemistry·Owen J SansomAlan R Clarke
Apr 1, 2006·Journal of Cellular Physiology·Yu-Feng DongHicham Drissi
May 2, 2007·British Journal of Pharmacology·P K Gillman
Aug 10, 2007·Nature·Curtis R Chong, David J Sullivan
Oct 2, 2007·Developmental Biology·Ju-Suk NamJeong Kyo Yoon
Apr 11, 2008·Molecular Biology of the Cell·Kyung-Ah KimArie Abo
Sep 5, 2008·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Mei ZhuDi Chen
Jan 31, 2009·Arthritis and Rheumatism·Peter KannuRavi Savarirayan
Jun 27, 2009·Chemical Communications : Chem Comm·Jacob AndersenKristian Strømgaard
Nov 27, 2010·Biochemical and Biophysical Research Communications·Keisuke ShinadaShigetsugu Hatakeyama
Dec 2, 2010·Nature Reviews. Rheumatology·Dick Heinegård, Tore Saxne
Jun 21, 2011·Lancet·Johannes W J BijlsmaFloris P J G Lafeber
Jun 23, 2011·Proceedings of the National Academy of Sciences of the United States of America·Kendra S CarmonQingyun Liu
Nov 4, 2011·The New England Journal of Medicine·Kithiganahalli N BalajiJagadeesh Bayry
Dec 20, 2011·Osteoarthritis and Cartilage·P M van der Kraan, W B van den Berg
Jun 12, 2012·Cell·Hans Clevers, Roel Nusse
Nov 16, 2012·Nature Reviews. Molecular Cell Biology·Christof Niehrs
Jun 13, 2013·Genes & Development·Po-Han ChenXiaolin He
Feb 18, 2014·Genes & Development·Wim de LauHans Clevers
Dec 8, 2015·Laboratory Investigation; a Journal of Technical Methods and Pathology·Yu UsamiMotomi Enomoto-Iwamoto
Dec 20, 2017·Molecular Medicine Reports·Weixiong LiaoXinzheng Wang

❮ Previous
Next ❯

Citations

Aug 20, 2019·Cell Communication and Signaling : CCS·Yudan WangFaming Tian

❮ Previous
Next ❯

Methods Mentioned

BETA
xenografts
ELISA
Protein Assay
Assay

Software Mentioned

Rspos
MetaMorph
NIH ImageJ

Related Concepts

Related Feeds

Adherens Junctions

An adherens junction is defined as a cell junction whose cytoplasmic face is linked to the actin cytoskeleton. They can appear as bands encircling the cell (zonula adherens) or as spots of attachment to the extracellular matrix (adhesion plaques). Adherens junctions uniquely disassemble in uterine epithelial cells to allow the blastocyst to penetrate between epithelial cells. Discover the latest research on adherens junctions here.

Cadherins and Catenins

Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to bind cells with each other. Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells: alpha-catenin can bind to β-catenin and can also bind actin. β-catenin binds the cytoplasmic domain of some cadherins. Discover the latest research on cadherins and catenins here.